Cell penetrating peptides were first discovered through efforts to describe how HIV (Human Immunodefficiency Virus) enters cells (Frankel 1988, Green 1988). This led to the discovery of the TAT (Trans-Activator of Transcription) protein encoded as the TAT gene within the HIV-1 virus as the protein responsible for cell penetration and the identification of the protein transduction domain, YGRKKRRQRRR, as the first cell penetrating peptide capable of entering the cell membrane (Lindsay 2002, Wadia 2003, Snyder 2004). Since the discovery of the TAT transduction domain, other cell penetrating peptides have been discovered (Saalik 2004).
Cell penetrating peptides have proven to be a useful tool for the delivery of proteins, small molecule drugs, antibodies, and other therapeutic compounds into cells and are currently being tested in clinical trials (Johnson 2011). Cell penetrating homing peptides have proven to be even more useful in that they can penetrate cells selectively by tissue type or areas of disease (Ruoslahti 2000, Kaplan 2005, Nishimura 2008).
While most cell penetrating peptides have been conjugated or electrostatically bound to the desired therapeutic payload (Niesner 2002, Brooks 2005), recent experiments have described the ability of a disease homing, cell-penetrating peptide CARSKNKDC (CAR) to enhance the ability of co-administered vasodilators (fasudil, Y-27632, imatinib, and sildenafil) to selectively lower pulmonary pressure in animal models of pulmonary arterial hypertension (PAH) (PCT/US11/26535) and additional experiments by Jirvinen and Ruoslahti have described CAR's ability by itself to promote wound healing (U.S. patent application Ser. No. 13/406,699).
However, the mechanism by which CAR enables the selective uptake of co-administered drugs and promotes wound healing has not been previously described. Furthermore the receptor to which CAR homes to is yet to be identified.
There is a need to understand the mechanism by which CAR works, and the receptor to which it binds. The benefits of identifying the mechanism are numerous, including developing novel diagnostic preparations used to aid in the development of new treatments for a variety of diseases. Identification of the receptor and understanding the related mechanism of action will lead to novel disease applications of cell penetrating peptides.